Li Aiqing, Zhang Jie, Ma Chao, Qi Lijuan, Hu Qiuming, Li Qian, Fang Yufei, Song Jianrui, Liu Yaobo, Zhang Yanling
School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China.
Wisdom Lake Academy of Pharmacy, Jiangsu Provincial Higher Education Key Laboratory of Cell Therapy Nanoformulation (Construction), Suzhou Municipal Key Lab of Metabolic Syndrome and Drug Research, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou 215123, China.
iScience. 2025 Apr 8;28(5):112385. doi: 10.1016/j.isci.2025.112385. eCollection 2025 May 16.
A distinguishing feature of neurons is the presence of long neurites that enable far-reaching communication. Establishing this complex morphology requires precise regulation of intracellular transport and signaling. Our study identifies DENND10, an ancient endosomal protein, as a crucial factor in shaping neuron morphology. DENND10 is a potential regulator of Rab GTPase signaling and interacts with the CCC/Retriever endosomal complex. Loss of DENND10 in a neuronal cell culture model resulted in shortened neurites. Quantitative proteomics revealed two distinct processes of neurite outgrowth: differentiation-induced biochemical changes and a pre-existing vesicular transport system modulated by DENND10. Mechanistically, both Rab27 and CCC complex subunit CCDC22 act downstream of DENND10 to support neurite extension. In primary cortical neurons, loss of DENND10 or CCDC22 led to shortened dendrites and impaired axon development. These findings provide a conceptual framework for neuronal morphogenesis during differentiation and highlight the critical role of DENND10/CCC in neurite extension.
神经元的一个显著特征是存在能够实现远距离通讯的长神经突。建立这种复杂的形态需要对细胞内运输和信号传导进行精确调控。我们的研究确定了一种古老的内体蛋白DENND10，它是塑造神经元形态的关键因素。DENND10是Rab GTPase信号传导的潜在调节因子，并与CCC/Retriever内体复合物相互作用。在神经元细胞培养模型中，DENND10的缺失导致神经突缩短。定量蛋白质组学揭示了神经突生长的两个不同过程：分化诱导的生化变化和由DENND10调节的预先存在的囊泡运输系统。从机制上讲，Rab27和CCC复合物亚基CCDC22都在DENND10的下游起作用，以支持神经突的延伸。在原代皮质神经元中，DENND10或CCDC22的缺失导致树突缩短和轴突发育受损。这些发现为分化过程中的神经元形态发生提供了一个概念框架，并突出了DENND10/CCC在神经突延伸中的关键作用。
